Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of death from cancer among males in the United States. It is well established that the normal development and maintenance of prostate is dependent on androgen acting through the androgen receptor (AR). AR plays such a central role in the biology and progression of prostate cancer, that androgen ablation therapy remains after >50 years the most effective treatment for metastatic prostate cancer. However, many men eventually fail this therapy and die of recurrent castrate-refractory prostate cancer (CRPC). CRPC is a lethal form of prostate cancer that progresses and metastasizes. This progression despite androgen deprivation is associated with an active androgen receptor (AR) - signaling pathway. At present, there is no effective therapy for it. Strategies to inhibit AR signaling and transcriptional activitation of target genes are thus, at the forefront of research in prostate cancer. With this proposal we show that the taxanes inhibit the transcriptional activity of AR, by impairing AR nuclear translocation and accumulation downstream of disruption of the MT cytoskeleton. Furthermore, our preclinical data clearly link taxane sensitivity to the effective inhibition of the lethal-phenotype-survival transcription factor AR. Thus, we propose that modulation of these transcription factors following Taxol- treatment determines clinical response. Given that the taxanes have recently emerged as the first class of antineoplastic agents to improve survival for metastatic CRPC, currently representing the standard of care for first-line treatment of CRPC, translation of these preclinical findings into the clinical setting will have a huge impact on the way PC is currently treated. Thus we plan to: Specific Aim 1) Isolate circulating tumor cells (CTCs) from CRPC patients both before and after they receive docetaxel-based therapy in order to investigate the molecular basis of clinical response. Specific Aim 2) Investigate the role of tubulin acetylation in taxane sensitivity in prostate cancer cell lines. Specific Aim 3) Investigate the molecular mechanisms underlying taxane-mediated inhibition of AR signaling in preclinical models of PC. Our proposal promises to identify the molecular determinants of taxane response in prostate cancer patients and help identify the subset of patients most likely to benefit the most from this treatment while sparing patients from the toxic effects of taxane-chemotherapy. Molecular understanding of drug-resistance in the clinic will lead to the identification of therapeutic interventions to overcome it.

Public Health Relevance

Strategies to inhibit androgen receptor (AR) signaling and transcriptional activation of target genes are at the forefront of research in prostate cancer, particularly for patients that die of recurrent castrate-refractory prostate cancer (CRPC). We show here that the taxanes inhibit the transcriptional activity of AR, by impairing AR nuclear translocation and accumulation downstream of disruption of the MT cytoskeleton and our preclinical data clearly link taxane sensitivity to the effective inhibition of the lethal-phenotype-survival transcription factor AR, thus suggesting that modulation of these transcription factors following Taxol treatment determines clinical response. Given that the taxanes have recently emerged as the first class of antineoplastic agents to improve survival for metastatic castrate-refractory prostate cancer (CRPC), currently representing the standard of care for first-line treatment of CRPC, translation of these preclinical findings into the clinical setting will have a huge impact on the way prostate cancer is currently treated.